Double Blind Study of Hydroxyzine, Promethazine, Secobarbital, and a Placebo for Pi~Eanaesthetic Medicatio N ~

DOUBLE BLIND STUDY OF HYDROXYZINE, PROMETHAZINE, SECOBARBITAL, AND A PLACEBO FOR PI~EANAESTHETIC MEDICATIO N ~

ALLEN B DOBKIN, M D, ~SHAN MALIK, M D., AND ~AC~3r~S Is~r~, M D

H'evaoxYzmE (Atarax@, Vlstarll@) has been under ehmcal trial to determine its efllcaey for pre-anaesthetae medacaUon on the bas.~ of its purported ne~oseda~jve, antihistaminic, anhspasmodle, anta-emet~c, and anaesthellc potentaatmg properties ~4 Laboratory studies have shown that the intravenous mleetmn of hydr0xy- zme causes a transmnt fall m blood pressure, an increase m coronary blood flow, and suppressmn of epinephrine-reduced ventrmula~l arr]hythmms 7 The pmtec- tare effect of hydroxyzme against arrhythmms is unrehable s In ehmeal tests, the therapeutic sedative dose has ~nrtually no antasml0gogue effect, 9 nor doe~s It chsturb the blood pressure even when circulatory stress of 60-degree head-up tilt is used t0 No undesirable side effects have been reported chmeally Promethazme (Phenergan@) has been used widely for pre-anaesthetm medaca- tlon dmmg the past ten years, ~x-~ paracularly when it as desirable to provade an antflustammm effect a7.~s It ~s a potent sedative, as deltermmed by the potentmi~on of ttnopental anaesthesm, s as a powerful antlslalogogue on account of its marked antxchohnerglc properties, ~9 ~0 and it has a mmmaal effect on the ctrculatory response to hlt 2~ The only drawback to ~ts routine u~e as the frequent complaint by patients of a "twltchy" feehng, whmh appears to be a common effeci of phenottnazme denvataves 2z 2~ Secobarbltal ~s a short-acting hypnotxc sedattve that has been used w~dely' for pre-anaesthet~e medmataon for many years It ~s recogmzed to be effective and has va-tually no undesirable effects, except that oceasmnally an elderly patient becomes confused during the half-asleep state that as reduced, whmh increases the ala~zn ff the patient as m an unfamflmr env~rorltment Tlh~s response as not uncommon w~th most of the barbiturate sedattves ~z Th~s report describes a double-bhnd study m whaeh hydroxyzme, secobarb~tal and a placebo (coded unlmowns) were compared w~th prornethazme (coded, but known) for pre-anaesthetac medmataon

~J[ETHODS Four hundred identical capsules were prepared of rwhlch 100 contained 50 mg ~From the Department of Anesthesiology, State Umve~slty Hospital, State Umvelrs~ty of New York, Upstate Medical Center, Syracuse, New York, 13910 499 Can Anaes Soe J, vol 12, no 5, September, 1965 500 CANADIANAI~,U~ST~!TS' SOCmT~ JOURNAL hydroxyzme (Vxstanl| 100 contained 50 mg promethazme t~Phenergan| 100 contained 100 mg secobarbital (Seconal| and 100 contained a placebo, lactose, and 2-ml brown ampoules were prepared, 100 containing 25 mg/ml hydroxyzme, 100 containing 50 mg/ml secobarbltal, and 100 containing a placebo, sahne Promethazme was prov:tded m cartridges containing 25 mg and 50 mg A random-number table was used to alsslgn the three drugs and the placebo to a hst of 400 consecutwe numbers Enwdopes contammg a capsule for evening oral administration, and an ampoule of the same compound (or cartridge of promethazme) for morning mtramusculal admlmstratmn were labelled with the assigned number and sealed The envelopes with the drugs were placed an the hospltal pharmacy and were req~alsltmned m numenca]l sequence A sealed copy of the drug code was kept by the pharmacist until the study was completed and aH data were tabulated Each day following pre-anaesthetm roull~ds, adult patmnts who were scheduled for a major electwe operation, who were ludged to be fit for the contemplated surgma| procedure, and for whom a genera| anaesthetm was considered appro- prmte, were assigned a consecutwe coded drug number Those patmnts who were to have mtracramal or cardmpu]m~l~raary procedures, and tllose who were to have short operatmns, were excluded ~lrom the study A capsule of the coded drug was always prescrxbed for oral admmlstratmn at the time of retmng, and a I volume of the drug not exceeding 2 ml Was ordered for mtramulscular injection one hour before the time os operatmn, along with 0 3 to 0 4 mg scopo|amme The volume of the coded drug pxescnbed was based upon the size, physique, and mental state of the patmnt Although all tlhe preparatmns used were an numbered envelopes, the nurse who administered pIlomethazme m each case would be able to identify thxs drug because it was slupphed m a cartridge instead of an ampoule, so on~ly three cff the four prepmatlons were considered as unknowns For each case that was studmd, a qtxeStlonnalre (see Fig 1) was completed by a graduate nurse who was trained s this study and assigned to it full-time She abstracted mformatmn from the patient's chart pre-operatlveiy, asked the patient direct questxons ~mmedmtely prmr to mductmn of anaesthesm, and questioned the anaesthesmlogast xmrned,ately following mductmn of anaesthesm All anaesthetms were superwLsed dlrectly by the authors, who used a uniform reduction procedure (gaHamme with thmpental ), and maintenance of anaesthesm was carrmd out m most cases w~th either mtrous ox~de-halothane c,r mtrous oxade-- methoxyflurane and controlled resplratmn m a non-rebreathmg system Post~ operatively, the anaesthetm chart and th e recovery room record were abstracted by the same nurse~ she wsxted the patmnt 24 hours postoperatively to obtain pertinent ~rfformatxon from the chart and to question the patient further, then the protocol was checked ~or completeness by one ot~ the authors At the conc]lusxon of the study, all the mformat~on on the protocol sheets of 373 o~ the patxents (:Fag 1) was tabulated and transferred to IBM c~xds The code was then ~evealed m order to analyze the data accordimg to the com- pounds All data were analyzed statastxcaHy ernploymg the cha-',quare test and p values ~ DOSKZN vt al. DOUBLE '501

PREMEDICATIO~ STUDY *l "'"= ~ ~"~ I-- iAia v

ligHT

OBED DRUG ~" ,t,.~.~ ITIME x s CAPSULE ~IVEX ?IME PRE IN~-dCTIOX ' OSE

.... =~ L=.===,,==,=====~J ,, 4.SSE~S~E~Tt | SLEEPING DRU6 USUALLY TAKER?

P. D.o AS.OG. R, EJ.RV NERVOUO EJ.OOMAL STABLE

3 TIME OF ONSET OF SLEEP ..... i ' '

4 THYROTO~ICITY PRESENT PAST DEGREE ,LO fT..RE _ _. L p

PRE INDUCTION DUES?IONS .~NAeS'rH~tlsr s OwN. mPRe.~sSiON ! -

I A~ YOU CO~VO~T~SLr [~VE~ r-]No WAS TI~[ PATIENT r'-]COblFBRTASL E [] UNCOMFORTABLE = ARE YOU WORRIEO~ []~B []NO [] WOrrieD AF PREHENSIVE [] URTROUBLEO 3 ARE you 1ENBr [-lvE~ ~.o F-IE~ITED EJREL''O 4 ARE YOU UNUSUALLY HAPPY? [~YES ~]NO EJNA~I. EU.,OR,: [] BERE.~ S ARE YOU UNUSUALLY SLEEPY? ~']YE3 ~XO [~DR~WSY BLI'EPY E~JWlDE AWAt~E 6 IS YOU R STOMACH UPSET? [-]YES [~]NO [] TA~KATI VE [] QU IF.T 7 mo YOU VOM,T? I--]TE~ LIND NAU.EI~TED [] YES [] NO oo~ou FEEL tIrED7 [~v~s ~No ABLE 110 RAISE EYELIDS I"]YES [~]NO soo ~ou s~[ DOUaLE~ []YEa ~.o ABLE 10 HAND 6RIP FIRMLY ["]YES [~]NO |0 ANY COMPLAINTS? [~YE= ~]NO

i ANAESTHETIST $ REPORT I t~ ADMISSION

BLOOD PRESSURE PULSE REGPIRA1 ION PRE ,SEDATION VITAL SIGNS PULSE __ RESPIRA1 ION BLOOD PRESSURE , I PRE INDUCTION

BLOOD PRESSURE PULSE REGPIRA't ION PUPIL SIZE__.__~..~

TIDAL VOLUME PRE SEDATION __ ML PRE I RDUCTII!IH -- ML I ' CHARTER OF INDUCTION ("-] SMOOT. ~SMOOTH Bur SLOW []D,EFICULT STOI'M 2 .EESS''ESE RE'ION

TIME IN MINUTES BETWEEN |M ~ &INOUCTION ~UETIO~ AGEI~IT----- | A;~AESTHETI~T S ESTIMATIOR OF AOEO UACY OF PREMEDICATION --] ADED UATE ]INADEQUATE.... [~] EXCESSIVE POST OPERATION QUESTaONS i WHAT DO YOU REMLMBER HAPPENING JUST PRIOR TO YOUR OPERATION~ I [] I M INJECTION 2. [~TRIP TO OPERATING ROOM 3 [] MOVEMENT TO OPERATING TABLE . EJW''NOOET'ON 113PLEA'ANT II~UHP'EASANT E]'NO'F'ERENTO"U"~NO~" POST OPERATBVE REPORT

1 [] AMNESIA 2 [~]URINARY RETENTION (DID THE PATIENT HAVE TO BE CATHETERIZED WITHIN |0 HRS OF OPERATION? i~.o) 3 [~ SHIVERIRG 4 I[---(NVPOTE.SIO. [] AFTZ~ ,.OUCTlOR ~ POST INDUCTION 5 [] NAUSI A AND VOMITING POST-OPERATIVE 6 [~] DELA~ IN AWAKENING AFTER COMPLETION OF OPERATION (FROM RECOVERY ROGM NOTES) ~IINUTEB

7 REMAR~ 5__, ,,I !

L ' *COMPARISON OF SECOBARBITAL HYDROXYZINE

Dobkln M D ..... Promethaz~ne a PLACEBO Allen B IMITIALS

I Protoco~ for compdmg data and quesuonna~e F[CLmE i i 502 CANADIAN ANAESTttETISTS' SOCIETY JOURNAL

TABLE I PATIENTS' ANSWERS TO DII~ECT QUESTIONS

Promt] thazme, Hydroxyzme, Secobarbttal, Placebo, 91 pts 96 pts 90 pts 96 pts (%) (%) (%) (%)

.... ' "i Discomfort 2 9 7 7 Apprehensmn 37 36 32 37 Exotement 33 35 25 24 Euphoria 5 2 5 4 Twedness 41 54 51 41 Sleepiness 33 41 41 41 Nausea 7 10 4 6 Vomited 1 1 2 1 Dlplopm 3 6 3 1 Complaints 22 14 17 28 I

TABLE I i

ANAESTHESIOLOGIST'S IMPRE%SION AS TO PATIENT'S STATE'

Promethazme, Hydroxyzme, Secobarbltal, Placebo, 91 pts 91~D pts 90 pts 96 pts (%) (%) (%)

Discomfort 8 g 5 6 Apprehensmn 38 42 27 35 Excitement 28 23 8 17 Euphoria 24 25 5 13 Sleepiness 39 57 60 59 Nausea 3 2 4 1 Talkatweness 6 12 8 9 Lid lag 1 3 1 7 Weakness 3 4 3 8

TABI}E III EFFECT OF PREMEDICATION ON VITA[ SIGNS BEFORE INDUCTION

[,~ ...... [ , ,, Promethazme, Hydroxyzme, Secobarbltal, Placebo, 91 pts 96 pts 90 pts 98 pts (%) ,(%/ (%) (%) i Hypotenslon (> 20%) 6 I0 11 12 Hypertension (> 20%) 12 8 10 7 Tachycardm ( > 20%) 4 9 14 6 Bradycardm (>20%) 3 1 5 9 I

TABLE IV I EFFECT OF PREMemCATION AND THm11'ENTAL INDUCTION ON BLO(m PRESSURE (>20% HYPOTENSION) DIURING FIRST 20 MINUTES

.... I ...... I Promethazme, Hydroxyzme, Secobarb~tal, Placebo, 91 pts 98 pts 90 pts J 96 pts , , ] Halothane 5/22 5/33 4/38 1/31 M ethoxyfl u ra ne 18/63 15/59 10/43 17/57 0 thers 1/6 1/4 1/9 2/8 DOBm~ et al DOUBLE BIJlND STUDr 503

TABLE V POSTOPERATIVE RESPONSES DURING FIRST 24 HOURS RIELATED TO PREMEDICATION : i I , ' ',., "" I Promethazmb, Hydroxyzme, Secobarbltal, Placebo, 91 pts 96 pts 90 pts 96 pt~ (%) (%) (%) (%)

Hypotensmn (> 20%) 2 2 2 7 Nausea ,and vomiting 23 25 25 24 Urinary retention 2 Z 4 2 Shivering 6 5 9 13 Delayed recovery (>30 mm) 16 32 29 31 Amnesxa 6 16 13 17 R~ctmg m O R 43 35 35 34

TABLE VI INCIDENCE OF VOMITING 24 HOURS POSqlOPERATIVELX

Promethazme Hydroxyzme Secobarbltal Placebo (91 pts) (96 pts) (90 pts) (96 pts) Vom,ted Vom,ted Vomited .... V omked Anaesthetm Cases (no) (%) Cases (no) (%) Cases ,(no ) (%) Cases (no) i(%) Halothane 22 7 32 33 5 15 I}8 9 24 31 7 22 Methoxyflurane 63 14 22 59 17 29 1t3 12 28 57 16 28 Others 6 4 2 -- 9 2 8 ,. ,,,

TABLE VII INCIDENCE OF DELAY IN RECOVERY FROM ANAESTHESIA

Placebo Promethazme Hydroxyzme Secobarbltal Awakened Awakened Awakened Awa!{ened Cases (no) (%) Cases (no) (%) Case,, (no) (%) Cases (no)' (%) F- 0 delay Halothane 22 11 50 33 12 36 38 15 39 31 14 45 Methoxyflurane 63 25 40 5'9 21 36 43 12 28 57 14 24 0-30 mm Halothane 22 7 32 33 13 39 38 17 45 31 11 35 delay Methoxyflurane 63 28 44 59 18 30 43 13 30 57 19 33 >30ram Halothane 22 5 23 33 8 24 38 6 16 31 6 19 delay Methoxyflurane 63 10 16 59 21 35 43 19 44 57 23 40 I

RESULTS Tables I to VII contain a summary of the pertinent data that were abstral~ted from completed protocols obtained on 373 patients Ampoule breakage accounted for 27 deletions Statistical analysis of the data showed that the four treatment groups had eqmvalent dlstnbutmns with respect to age, sex, dosage, and primary anaestlmtm given, mdmatmg satisfactory random~zataon i 504 CANADIAN ANAESTHETISTS' ~ JOURNAL Preinduction Questions (see Table I) A value of cba-square equal ~ or gIeater than 60 mdxcated a statastacally significant d~fference between the drugs at 05 probabihty level The chx-square test showed that there was no signtfican!t difference between the drugs and the placebo m the development of worry, euphorm, upset stomach I, vomiting, and daplopm Fewer patients complained of &scomfort with the placebo, and slgmfieantly fewer patients complamed of tenseness or excitement wxth hydroxyzme and secobarbltal (p < 05) Slgndlcantly more pataents were tired or sleepy with promethazme, hydroxyzme, and sec0barbltal than with the placebo (p .01 ) and most complaints (usually that the patient did not sleep well) were found with the placebo and with secobarbltal (p -- 02) Considering all the pre- anaesthetic questaons each patient was asked, and relating the answers to the preoperatave sedation, we may rank the patients' preference for hydroxyzme or promethazme as higher than for secobarbltal or the placebo The anaestheslologxsts' Impressions (see Table II) m a sxmdar analysis shqwed no slgmficant differences m the incidence of discomfort or nausea, Fewer patients were apprehensive, excited, and euphoric wath hydroxyzme than wath the other agents used (p < 001), and apparent sleepiness occurred least often wltl~ the placebo (p < 001), while manifestations of agltataon (apprehension, euph0rla, talkataveness) were most common with promethazme (p < 02) Considering the over-all answers expressed by the anaestheslologlsts, hydroxyzme and secobarbltal would be ranked higher than promethazme and the placebo Combmmg the results of the answers by the patient and the anaestheslologlst, the sedatwes may be ranked as follows ~hydroxyzme, secobarbltal, promethazme, placebo

Effect of Premedwat~on on V~tal S~gns be[ore and after Inductton of Anaesthesia (see Tables IH and IV) The number of pataents showing an Increase, a decrease, or no change m blbod- pressure levels between pre-sedat~on and pre-mductlon was not statistically slgnflcant although mild hypotenslon occurred less frequently wxth the placebo Tachycardla occurred more often with hydloxyzme, and bradycardm occurred more often with secobarbltal, but m no case were these alterations alarming Hypotenslon of greater than 20! per cent following mduct~on of anaesthesm appeared to be quite unrelated to the pre-operatlve sedatwe used That ~s to say, it appeared unhkely that any of the sedatwes (including the placebo) affected the blood-pressure response to the induction of anaesthesm, and m none of the eases m this study did an alarming fall m blood pressure ( > 30 per cent) occur lmmedmtely following the reduction of anaesthesm

Postoperatwe Report (see Tables V and VI) Chl-square tests did not reveal any appreciable difference m postanaesthetlc incidence of hypotenslon or nausea and vomttang m the first 24 hours that could be related to the premedlcants The groups were too small to relate the incidence of nausea and vomiting to the primary anaesthetic alone roman et al DOUBLE BLIND ~I,TUDS~" 505

i Amnesm occurred more frequently m the patients ~tat received a drug for plemechcatlon than those that received the placebo (p < 001), urinary retentmn reqmrmg cathetenzatmn occurred more ofte~ ~ th(I pahents who recewed [pro- methazlne (p < 05), and postanaesthetm stnv~en(ng occurred more often m! the pataents who received secobarbttal (p < 01 )

Ir~:,dence of Delay m Awakemng after Termmatmn ojF Anaesthesia Fewer patients had zero delay m reacting m the operating room (1 e, were responsxve to questmns and instructions) that received premedlcant drugs than those that received the placebo (p < 01) When the comparison was made with regard to recovery within 30 minutes of termination of the anaesthetic, tins &florence was striking (p < 001) When this effecl wa,~ related to the primary anaesthetics used, there was no consistent dafference m effect (See Table VII )

DrscussgON It is now an estabhshed practice for the chmclan to take, every measure possible to ehmmate pre]udace and baas from the evaluation of new therapeutic measures 25 28 Although the double-blind techmque is 1deal when the primary effects of the drugs to be compared are very slmflarl, at may not be a fool-proof devace when each of the drugs has certain side effects l hat the astute chmcxan can recognize 23 27 Nevertheless, ff the study as well desagned and carefully controlled, and ff a proper balance is struck among the psychologmal and physm- logical factors that may be measured or evaluated su/b]ec~lvely and oblectwely, it as possible to approach the correct answer wath somewhat more assurance than li one rehes purely on ehnacal ampressmns 2s The authors recognized beforehand that at was esl~entlal to ensure sedataon to some degree m every patient, because this is one of our primary duties On the basas ot past expealence, it was decaded therefore that ewery patient m thas study should receave scopolamine as the antlslalogogue along ~th the placebo or any of the three sedatwes, because scopolamine not only has some sedative properties of ats own, but it also makes ~t difficult to adentffy the presence of other drugs winch have predominantly hypnotic properties 2r,29 The obvious disadvantage to using tins method as that at tends to "da]ute" changes an effect that dlfferen~aate the drugs that are being tested and compared to an mort placebo However I we took into account the knowledge that as many as 50 per cent of the pahents might appear to be "sedated" wath the placebo Mone, and that the broad approac!h to evaluating several psychologmal factors both sublecttwely and oblectlvely would give us enough mformatmn to d~fferentmte the placebo-,,copolamme effect t!rom that produced by the combmatmn of scopolamine and one of the three sedatives A11 the recolded factors were revaewed with respect to the main condlhons one de,,lres m a pataent lespondmg to a premedacant drug, such as general b0ddy comfort, sleepiness, and amnesia, the exclusmn of excitement, euphoria, nausea, ol other annoying complaints, the absence of gros,,~ changes m blood pressure and pulse rate before and after mductmn of anaesthesm, and the uncommon occuraence of unexpected delay m recovery from anaesthesm It was ewdent that 506 CANADIAN ANAESTHETISTS' SI~IETY J~OURNAL the placebo was less effectave than the three drugs that were tested although the over-all mcxdence of apprehension was disappointingly high It was also evident that promethazme appeared to be less effective in reducmg the mcldence of apprehensmn, excitement, euphorm, and talkata~eness than the :other sedatlyes, even though the occurrence of sleepiness and ttredness were comparable ExCept for a somewhat higher incidence of complaints by the patients who recexved secobarbltal (usually related to madequate overmght sleep), there was h~le choice between It and hydroxyzme These findings are m essentaal agreement with the observations of B~zzam and assocmtes ~ In our study, no par'tent had an untoward response to any of the premedlcants It ~s apparent that it wdl take a much more widely documented experience to determine whether hydroxyzme has m fact much greater efficacy than secobarbltal or promethazme As Modell has stated, "Do not fear about the good drugs, they will be recognized ff they are placed m proper hands, will make themselves felt prompytl, wfll.~be recogmzed for what the~y are,, and they will surwve Remember there ts no guarantee that a new drug is better than an old one, the chances are less than even, and ff you throw the weight of your experience into the balance, the odds agamst ~t are still longer Therefore, until the evidence als m, until after a drug's probataonary period is over, I suggest that the value of experience be held m proper esteem and take precedence over shakaly estabhshed claims and hurried use of new drugs -80

SUMMARY AND CONCLUSIONS A double-bhnd test was employed to compare the effect of three unknowns (hydroxyzme, secobarbltal, and a placebo~ with promethazme for pre-anaesthetac sedataon on 373 adult patients who were being prepared for a malor electave operation under general anaesthesia Each patient was gwen a capsule the n~ght before, by mouth, and one hour before the operation the same compound was gwen mtramuscularly, with scopolamine, to ensure a/i adequate antlslalogogue effect and to help m preventing the identification of the sedatwe compound Data were collected on a special protocol which was completed for each patient by a nurse who was trained m this work The protocol contained reformation recorded from the matial pre-anaesthetic visit, before reduction of anaesthesm (answers to direct questaons by tile patient), following reduction of anaesthesm (answers to questions by the anaesthesl61oglst), and changes in vatal signs and symptoms immediately after anaesthesm and during the first 24 hours after the anaesthetic Upon completion of the study, t]he data were tabul~tted and transferred to IBM cards All data were then anallyzed statistically by means of the chl-square test The analysis revealed Ithat the patwnts seemed to t eel better wlth hydroxyzme than with promethazme~ secobarbltal, or the placebo, m that order, whereas with the anaestheslologlst the order of preference was hydroxyzine, seeobarbltal, promethazme, and placebo. When the results were combined, the order preferred by the anaestheslologlst appeared to be the more vahd None of the sedatwes appeared to have an apprecmble effec| on the blood pressure or pulse rate before or after reduction of anaesthesm, nor dad the pre- DOBraN et al DOUB~ BLIND STUDY 507 me&cant drugs appear to influence the incidence of postanaesthetlc hypotensmn or nausea and vomiting On the other hand, amnesia occurred more frequently in the patients who recewed drugs for sedatmn, and the incidence of slow recovel3~ from anaesthesm was s~gmficantly h:gher among these as compared to the patients who reeewed the placebo The only other postoperatwe symptoms that m~ght be relal.ed to the sedatwes were the occurrence of shwe~mg, which was h~ghest among those pat:ents who received secobarbatal, and u:anary retentmn (reqmrmg catheter~atlon), wh:ch occurred most often w~th those receiving promethazme Although the preferred order of the three sedat~les and the placebo was stat:st:cally vahd, the over-aLl &fferences were not great Only by careful documentation of the effects m a far larger series of patients wall ~t be poss~b|e perhaps to obtain an uneqmvocal answer

P~sr~ Nous avons falt une 6tude ~ double-lnconnu pour comparer les effets de trois substances mconnues (l'hydroxyzme, le s6cobarbltal et le placebo) avec la prom6thazme en prdm6&catlon chez 373 adultes qm deva:ent sublr une op6ra- t:on majeure sous anesth6s:e g6n6rale La vellle, chaque malade a pns par ',la bouche une capsule et, une heure avant l'op6rat:on, la m4me substance add~tmn- n~e de scopolamine a 6t6 mlect6e dans le but de dunmuer la s6er6~on sahvar:e et d'emp4cher lhdent~catmn de la substance s6datwe Les donndes ont 6t6 recueflhes sur uno fe~_~_d!e de protocole spdcmle pour chaque malade et mscntes par une ~euflle de protocole sp6cla]e pour chaque malade et mscntes par une mfirm:~re qual~6e pour ee travail Ce protocole cont:ent des renselgnements recueflhs ~ partar de la prema&e v:s:te pr~anesthds:que, avant l'mductmn de l'anesth6s:e (les r6ponses aux quest:ons pos4es par le malade), ~ la state de lhnductlon de l'anesth6sle (les r6ponses aux questions pos6es par les anesth6slo- log:stes ), les changements des s:gnes wtaux et des sympt~]~mes amm6dlatement apr~bs l'anesth6sle et durant les 24 premlbres heures apr~s l'anetsth6,~m A la fin de l'6tudte, les donn6es ont 6t6 accumul6es et ampr:m6es sur des caites IBM Toutes les donn~es ont alors 6td analys6es stat~st~quement en emp|oyant le test "ch~ square'" L'analyse a r6v61~ que les malades semblaaent se sent~r m~eux avec l"hydroxyzme qu'avec la prom&hazme, le s6cobarb~ta~ et le placebo, dans cet ordre, alors que d'aprbs le ]ugement de l'anesth6s~ste, l'ordre de pr6fdrence dta~t l'hydroxyzme, le s6cobarb~ta~, la prom~thazme et te placebo Lorsque les r6sultats furent corn- bm6s, l"ordre pr6f6r6 par l'anesth6smlog:ste semble 4tre le plus vahde Aucun des s6datffs ne semble produtre un effet sens:b]le sur la pressrun art6r~elle ou sur la wtesse du pouls avant ou apr~s l'mduct~on de l'anesth4,s~e, fl en est ams~ pour ~es me&careen' t s donn6s en pr6m6&cat~on, fls ne semblent pas avo,~r d'mfluence sur ]'hypotens:on postanesth6s~que, les nausdes et les vom~ssements D'autre part, nous avons observ6 plus souvent de l'amn6s~e chez les malades qm ava:ent ~equ la m~&cat~on s~datwe, et ~es r~ve:ls tardlffs se sont prodmts beaucoup ptu~ ff~quemment chez ces maIades s: on les compare a ceux qm ont reCu du placebo Les seuls autres symptom^ e s postop~ratotre~ qul peuvent se rattacher aux s6datffs sont le fnsson qm a ?et6 plus ~r~quent chez le,; malades qu~ ava:ent CANADIAN ANAES~TISTS' SOCIETY JOURNAL re~u du s6cobarbital, et la r6tentaon d'urme (n6cessltant une son te) qul est sur. venue la plupart du temps chez eeux qua avalent pns de 1~ prom&hazme Blen que l'on place les trms s6datah et le placebo dans un ordl e de pr6f6retncc statastlquement vahde, les dtff6renees g6n6rales xl'6tamnt pas gra: tdes POur avonI une r6ponse non 6qmvoque, d faudm~t une documentatmn solgt 6e sur les e~et, de ces m6dlcaments pour un groupe de malades beaucoup plus eoi tsxd6rable

ACKNOWL]IDGMENTS Tbas work was supported by a grant m aid made by Pfizer Laboratorms, New York City Mtss Christina Blsset, R N, was ot~ great help by ddlgently and conscientlonsly lntervmwang the patmnts and abstracting the records during tills study

REFERENCF.S 1 BXZZARRI,D, LATTERI, F S, SCH~?C~KI~ER,~A, FIERRO, F E, GUIFFRIDA,J. & BEBGER, H C Preanesthetic Medmahon With Intrawmous Hydroxyzme Anesth Analg, 40 378 ( 1961 ) 2 BIZZARHI,D, GUIFFRIDA,j, Fmrmo, F E, & LATTEm, F S Preanesthetm Medmation Wlth Intramuscular Admlmstratmn of Hydroxyzme Hydrochlonde A Parallel Double Blind Study of Hydroxyzane Hydrochlo~lde, Mependine Hydrochl0nde, Hydroxyzane Hydrochlonde and Mependme Hydrochlonde, Secobarbltal Sodium and a Placebo Anesth & Analg 42 316 (1963) 3 Dob~n, A B, ISRAEL, J s, & Cmsw,cK, V G Prolongation of Ttu0pental Anaesthesia with Hydroxyzme, SA 97, Thmthylperazme, end Thlondazme CanadAnaesth Soc J 9 342 (1962) 4. GRAVY, R W & RmH, A R A Prelmunary Rel~rt on the Use of Hydroxyzme (Vlstard) as a Premedlcant for Surgical Patmnts J M A Alabama 29 377 (1960) 5 SamlNB~no, N & HOLZ, W G Preoperative Preparatmn for Tonsdlectomy wxth Hydroxy- zme Hydrochlonde in Pediatric Patients New York J Med 60 691 (]960) 6 WEYNE, F & ROVSSEL, J L Hydroxyzane m Anesthesiology Bruxelles Med 37 51 (1957) 7 H~rrcrmoN, D E, SCalAmN~., A, & Mom~is, D L Cardiovascular A ctton of Hydroxy- zane J Pharmacol b Exper Therap 118 451 (1956) 8 DOBXlN, A B & ISRAEL, J S The Effect of SA 97, Perphenazme, and Hydroxyzme on Epinephrine-Induced Cardiac Arrhythmms during Methoxyflurane Anaesthesia m Dogs Canad Anaesth Soc j 9 36 (1962) 9 DOBXIN, A B, WOODWOaTH, H, & ImaAEL~ J S The Antlsmlogogue Effect of Hydroxy- rune, Thmthylperazme, and SA 97 Canad Anaesth Soe J 9 234 (1962) 10 DoBrd~r_, A B, RoBmotm, H J, & ISRAEL, J S Ctrculatory RespOnse to Tit ~Wlth Hydroxymne, Tluethylperazme Maleate, SA 97, and Perphenazme Anesth & A~nalg 42 225 (1963) 11 ADELMArr M H, JACOBSON, E, LmF, P. A, & MILLER, S H Promethazme Hydro- chloride m Surgery and Obstetrics J A M,A 169 5 (1959) 12 CARROLL,J J & HUDSON, P W Chl0rpromazme and Promethazme m Obstetrics C~nad Anaesth Soe J 2 340 (1955) 13 CmmOLL, J J & Mona, R S Use of Promethazme (Phenergan) Hydrochlonde m Obstetrics JAMA 168 2218 (1958) 14 SAvow, M S & FRYE,J Pre-Operatlve ~edatmn and Productton of a Quiescent State in Children Promethazane-Mependme.Scol~Mamine Sedation J.4 M A 164 1729 ( 1957 ) 15 WATROUS,W G Promethazme in Clm,cal Anesthesia Anesth & Analg 36 38 (1957) 16 DOBKIN, A B Potentlatton of Tbaopentone Anaesthesm Comparison of Promethazme, Chlorpromazme, Perphenazme, Fluphen!azme, Thlopropazate, Plpamazme and Trffiu- promazme Bnt J Anaesth 32 424 (1960) DOBKIN et al DOUBLE BLIND STIIIDY 509 17 HALPElaN, B N & HAMStmCF.a, J A New Synthebe Ant;lhlstammm Substance Der:ved from Phenothlazme (Phenergan, 3277RP) Canad M A J 59 322 (1948) 18 HEnXmZIMEa,H Antihistamines m Bronchial Asthma Bnt M J 2 901 (1949)

]3 63 (1958) 20 N~ANjO, P & D~ NAn~Uo, E B Local Anaesthetic Ac~wtty of Some Antlhlstammes and Its RelatJonship with Antihlstammlc and Antichohn~irgm Actlwties Arch mternat pharmacodyn 113 313 (1958) 21 DOBr~IN, A B, KErr., A M, & WONC, G Clrculatory Re,tponse to Tilt with Phenothm- zmes Anaesthema 16 160 ( 1961 ) 22 DoB~w, A B Sedahves, Analgesms, Antidotes, and then Interaction Canad Anaesth Soc J II 252(1964) 23 DOB~tN, A B & PtramN, N Double Bhnd Study of Phenq~thmzmes Used m Pr~e- Anaesthetxc Medmatmn A Chrncal Evaluation of Prometha~me (Phenergan| Pm- mazme (Sparme| Proclorperazme (Stemetfl| and Levomepromazme (NoZx- nan| Canad Anaesth Soc J 7 158 (196(}) 24 F~SHEa, R A & YAT~.S F Statishcal Tables for Agrmultural, Bmlogmal and Medlr~a] Research Edinburgh Ohver & Boyd (1953) 25 Br.Ecr~n, H K Experimental Pharmacology and Measullement of the Sublectave Be- sponse Scmnce 116 157 (1952) 2~ MODELL, W & HOUDE, R W Factors Influencing Chmcal E valuatmn of Drugs wath Specml Reference to the DoubIe-Bhnd Techmque J A I~ A 267 2190 (1958) I 27 DoBt~m, A B, ISRAEL, J S, & BILKS, P H Double Blind Study of Methotrnneprazane, Morphine, and Mependme for Preanesthetm Medmatmn Ane,~th & Analg (m press) 28 HEroiNe, F H Response dunng Anesthesia and Surgery Psychosom Med 18 243 ( 1956 ) 29 PEDEI~EN, J E P Scopolamine As Sole Pre-Anesthehc Medmation Acta Anaesfh Scandmav 7 121 (1963) 30 MODELL,W Safety m New Drugs J A M A 290 141 (1964)